Glycemic Control and CVD: Making Sense of the Studies

Dr. Ford is a clinical pharmacy specialist
at the University of North Carolina
Hospitals and an assistant professor
at the University of North Carolina
Department of Family Medicine.

Patients with diabetes have a 2-
to 4-fold higher risk of stroke
and death from heart disease
compared with people without diabetes.
Hyperglycemia also causes damage
to the microvasculature, leading
to blindness, kidney disease requiring
dialysis, neuropathy, and amputations.
These risks can be reduced with
a combination of exercise, healthy
eating habits, and medications.

Another important factor in improving
diabetes care is education to
empower patients with information to
better manage the disease themselves.
Pharmacists are in a unique position to
educate patients on medicines for glucose
control and those used to manage
or prevent complications of diabetes.

Improving glycemic control is known
to reduce the risk of microvascular
complications of diabetes, but previous
studies have failed to demonstrate
a reduction in cardiovascular disease
(CVD) with improved glycemic control.
The United Kingdom Prospective
Diabetes Study (UKPDS),1 published
in 1998, showed a 25% reduction in
microvascular complications—but no
difference in macrovascular disease—in patients with type 2 diabetes randomized
to intensive glycemic control
with insulin and sulfonylureas, compared
with standard control. Patients
in the intensive control group achieved
a mean A1C of 7%, compared with 7.9%
in the standard control group. Current
American Diabetes Association (ADA)
guidelines2 recommend targeting a goal
A1C of <7% in the general population of
patients with type 2 diabetes, although
most other organizations recommend
lower A1C targets.

Two recently reported trials—ACCORD3
and ADVANCE4—were
designed to test the effects of more
intensive glycemic control on vascular
outcomes in type 2 diabetes patients.
The ACCORD trial received extensive
media attention when a press conference
was held in March announcing an
increase in mortality in the intensive
control group. The ADVANCE study,
which did not demonstrate an increase
in mortality in the intensive control
group, was published simultaneously
with ACCORD in June 2008.

The ACCORD Trial

The ACCORD trial3 is a prospective
randomized study of 10,251 patients to
determine whether intensive glycemic
control (goal A1C of <6%) would reduce
the rates of cardiovascular events compared
with standard therapy (goal A1C
of 7%-7.9%) in patients with type 2 diabetes
and CVD or at high risk for vascular
events. After a mean of 3.5 years of
follow-up, the rates of all-cause mortality
were 5% in the intensive glycemic
control group and 4% in the standard
therapy group (hazard ratio, 1.22; P =
.04), indicating an increase in 1 death
per 100 patients treated with intensive
therapy over 3.5 years. An increase in
cardiovascular mortality was noted with
intensive therapy compared with standard
therapy (0.79% annually vs 0.56%;
hazard ratio, 1.35; P = .02). Of note,
annual rates of nonfatal myocardial
infarction were decreased with intensive
therapy compared with standard
therapy (1.11% vs 1.45%; hazard ratio,
0.76; P = .004).

Median A1C levels at follow-up
were 6.4% and 7.5% in the intensive
and standard therapy groups, respectively,
from a baseline of 8.1%. Rates
of hypoglycemia requiring assistance
were significantly higher in the intensive
control group compared with the
standard control group (16.2% vs 5.1%;
P10
kg was more common with intensive
therapy—28% over 3.5 years, versus 14%
in the standard group. Despite many
analyses, the investigators were unable
to determine an explanation for the finding
of increased mortality with intensive
therapy, including an analysis of the
potential contribution of specific drugs
such as rosiglitazone. Data on microvascular
disease were collected during this
study, but have not yet been published.

The ADVANCE Trial

The ADVANCE trial4 also aimed to
determine the effects of intensive glucose
control on major vascular events
in patients with type 2 diabetes. Similar
to the ACCORD study, patients were
included only if they had documented
macrovasular or microvasular disease or
risk factors for vascular disease; >11,000
patients were enrolled. ADVANCE participants
had lower A1C levels at baseline
and a shorter duration of diabetes and
could not be treated with insulin prior to
entry. Patients randomized to intensive
glucose control were treated with a specific
sulfonylurea.gliclazide.plus other
medications determined at the discretion
of the treating physician to a goal A1C of
.6.5%. Patients randomized to standard
glucose control were treated to a goal
A1C determined by local guidelines.

After a median duration of follow-up of
5 years, the median A1C in the intensive
glucose control group was 6.3%, compared
with 7.0% in the standard glucose
control group, from a baseline of 7.2%.
Patients in the intensive control group
experienced significantly fewer major
microvascular events (mostly a reduction
in new or worsening nephropathy) than
those in the standard control group (9.4%
vs 10.9%; hazard ratio, 0.86; P = .01), but
no difference was reported in the incidence
of major macrovascular events.

In contrast to findings in the ACCORD
trial, investigators found no difference in
all-cause mortality between the 2 groups
(8.9% in the intensive control group vs
9.6% in the standard control group; hazard
ratio, 0.93; P = .28). Severe hypoglycemia
(defined as hypoglycemia requiring
help from another person) occurred
at least once in 2.7% of patients in the
intensive control group and in 1.5% of
patients in the standard control group
(hazard ratio, 1.86; P

Other Studies

Additionally, results of a 10-year postintervention
follow-up of intensive glucose
control in the UKPDS were recently
published.5 By the end of the first year
after study completion, the difference in
A1C from the original study (7% vs 7.9%
in the intensive control group vs conventional
control) had disappeared, and
similar A1Cs were maintained through
the 10-year postinterventional followup.
At 10 years, patients in the intensive
control group maintained a lower risk of
microvascular disease, and reductions in
the risks of diabetes-related death, death
from any cause, and myocardial infarction
emerged in the group of patients
originally allocated to intensive control.
These data indicate that the known
microvascular benefits of intensive glycemic
control persist despite loss of glycemic
control, and although improved
glycemic control may not have an immediate
effect on macrovascular disease,
there may be long-term benefits.

Finally, data from another trial
designed to test the effects of intensive
glycemic control on macrovascular disease,
the Veterans Affairs Diabetes Trial
(VADT), were presented recently at the
ADA Scientific Meeting in June.6 The aim
of this trial was to lower A1C levels in the
intensive treatment group to as close to
normal as possible. Patients in the intensive
control arm achieved a mean A1C of
6.9%, compared with 8.4% in the control
arm. No statistically significant reduction
in cardiovascular events was seen, which
is consistent with the results of ACCORD
and ADVANCE. Further data will be available
when VADT is published.

Counseling Patients

The data from these recent studies create
more questions than answers. Mounting
evidence has been reported that improving
glycemic control does not substantially
decrease the risk of macrovascular
disease, except perhaps in individuals
with earlier disease and longer follow-up
and even then at modest effect.

The ACCORD trial and the VADT
suggest that inherent risks may exist
with more intensive glycemic control,
although these risks were not apparent
in the gentler ADVANCE trial. This disparity
may be due to differences in the
medications and intensity of application
to lower A1C, differences in preventive
medications, or differences in the populations
between the 2 studies.

In light of the increased mortality with
lower A1C levels in the ACCORD study,
it is likely prudent to follow the ADA
recommendations to target an A1C of
<7% instead of more intensive glycemic
control, until more information is available
on the risks and benefits of lowering
A1C levels further. When counseling
patients, it is important to emphasize the
known benefits of glycemic control in
reducing microvascular complications
of diabetes. Patients should be advised
not to stop their diabetes medications
without first talking to their doctor or
other diabetes provider.

Additionally, as more information is
available on the risks and benefits of
intensive glycemic control, it is important
to remember those interventions
that are known to reduce the risk of CVD
in patients with diabetes.smoking cessation,
aspirin, and treatment of hypertension
and dyslipidemia.

Acknowledgment: John Buse, MD,
PhD, professor and chief, Division of
Endocrinology and Metabolism, Department
of Medicine, University of
North Carolina, and president, Medicine
and Science, American Diabetes
Association, for his review, commentary,
and expertise in the preparation
of this manuscript.